A single bout of exercise improves motor memory

Regular physical activity has a positive impact on cognition and brain function. Here we investigated if a single bout of exercise can improve motor memory and motor skill learning. We also explored if the timing of the exercise bout in relation to the timing of practice has any impact on the acquisition and retention of a motor skill. Forty-eight young subjects were randomly allocated into three groups, which practiced a visuomotor accuracy-tracking task either before or after a bout of intense cycling or after rest. Motor skill acquisition was assessed during practice and retention was measured 1 hour, 24 hours and 7 days after practice. Differences among groups in the rate of motor skill acquisition were not significant. In contrast, both exercise groups showed a significantly better retention of the motor skill 24 hours and 7 days after practice. Furthermore, compared to the subjects that exercised before practice, the subjects that exercised after practice showed a better retention of the motor skill 7 days after practice. These findings indicate that one bout of intense exercise performed immediately before or after practicing a motor task is sufficient to improve the long-term retention of a motor skill. The positive effects of acute exercise on motor memory are maximized when exercise is performed immediately after practice, during the early stages of memory consolidation. Thus, the timing of exercise in relation to practice is possibly an important factor regulating the effects of acute exercise on long-term motor memory.     

Sequence specific motor performance gains after memory consolidation in children and adolescents

Memory consolidation for a trained sequence of finger opposition movements, in 9- and 12-year-old children, was recently found to be significantly less susceptible to interference by a subsequent training experience, compared to that of 17-year-olds. It was suggested that, in children, the experience of training on any sequence of finger movements may affect the performance of the sequence elements, component movements, rather than the sequence as a unit; the latter has been implicated in the learning of the task by adults. This hypothesis implied a possible childhood advantage in the ability to transfer the gains from a trained to the reversed, untrained, sequence of movements. Here we report the results of transfer tests undertaken to test this proposal in 9-, 12-, and 17-year-olds after training in the finger-to-thumb opposition sequence (FOS) learning task. Our results show that the performance gains in the trained sequence partially transferred from the left, trained hand, to the untrained hand at 48-hours after a single training session in the three age-groups tested. However, there was very little transfer of the gains from the trained to the untrained, reversed, sequence performed by either hand. The results indicate sequence specific post-training gains in FOS performance, as opposed to a general improvement in performance of the individual, component, movements that comprised both the trained and untrained sequences. These results do not support the proposal that the reduced susceptibility to interference, in children before adolescence, reflects a difference in movement syntax representation after training.     

Berberine improves glucose metabolism through induction of glycolysis

Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3-O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser307/312), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for > or =16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.     

Photoperiod controls the induction,retention, and retrieval of antigen-specific immunological memory

Changes in day length affect several measures of immunity in seasonally breeding mammals. In Siberian hamsters (Phodopus sungorus), short day lengths suppress specific secondary antibody responses to the keyhole limpet hemocyanin (KLH) antigen and enhance cutaneous delayed-type hypersensitivity (DTH) responses to dinitrofluorobenzene (DNFB). These experiments tested whether day length affects secondary antibody and DTH responses by altering immune function solely during the interval after the initial exposure to each antigen, solely during the interval after the second exposure, or during both stages of the respective immune responses. Adult male Siberian hamsters were exposed to either a long (16 h light/day; LD) or a short (8 h light/day; SD) photoperiod for 7.5 wk before receiving an initial exposure to each antigen (KLH injection, cutaneous DNFB treatment; separate groups of animals for each antigen). A subset of LD hamsters was transferred to the SD photo-period, and a subset of SD hamsters was transferred to the LD photoperiod. Other hamsters remained in LD or SD. Eight weeks later, all hamsters were challenged with a second subcutaneous injection of KLH or a second application of DNFB to the ear, and immune responses were measured. Exposure to SD during the primary antibody response did not affect secondary IgG responses, but SD exposure during the secondary response significantly suppressed IgG production independent of day length during the initial KLH treatment. In contrast, exposure to SD during the DNFB challenge enhanced the ensuing DTH response, but this enhancement depended on the photoperiod prevailing during the initial exposure. Exposure to SD during the sensitization stage did not enhance DTH in hamsters subsequently exposed to LD. The data suggest that short photoperiods have enduring effects on immune responsiveness and on the establishment and retention of immunological memory.     

Sex differences in the long-term effect of preweanling isolation stress on memory retention

Social experiences during development can powerfully modulate later neuroendocrine and behavioral system. In the present study, male and female rat pups experienced daily bouts of social isolation for 6 h per day or control conditions during the third postnatal week. Performance on a 12-arm radial maze with 8 arms consistently baited with food reward was examined in adulthood. During the social isolation, both male and female pups exhibited a significant increase in plasma corticosterone levels. When tested on the radial arm maze as adults, the performance of female rats that had experienced social isolation during development was not affected; however, male rats in the isolation condition initially exhibited impairments in working memory but not reference memory. Despite achieving comparable asymptotic levels of performance on the maze, male rats that experienced social isolation during the third week demonstrated disruption in working memory retention when radial arm maze trials were interrupted after the fourth arm choice. Thus, while male rats that experience social isolation during the third week of life eventually perform comparably to controls on the standard radial arm maze task, their ability to retain information over a delay remains impaired. These findings highlight an important sex difference in the long-term effects of stress during this period of late preweanling development.     

Cerebellar function in consolidation of a motor memory

Several forms of motor learning, including classical conditioning of the eyeblink and nictitating membrane response (NMR), are dependent upon the cerebellum, but it is not known how motor memories are stored within the cerebellar circuitry. Localized infusions of the GABA(A) agonist muscimol were used to target putative consolidation processes by producing reversible inactivations after NMR conditioning sessions. Posttraining inactivations of eyeblink control regions in cerebellar cortical lobule HVI completely prevented conditioning from developing over four sessions. In contrast, similar inactivations of eyeblink control regions in the cerebellar nuclei allowed conditioning to develop normally. These findings provide evidence that there are critical posttraining memory consolidation processes for eyeblink conditioning mediated by the cerebellar cortex.     

Transgenic expression of androgen receptors improves spatial memory retention in both sham-irradiated and 137Cs gamma-irradiated female mice

Using a water maze, it has been shown that both wild-type and apoE4-expressing female mice are at greater risk of developing age-related hippocampal-dependent impairments in spatial learning and memory than age-matched male mice of the same genotype. In addition, apoE4-expressing female mice were more sensitive to 137Cs gamma-radiation-induced impairment in spatial learning and memory than age-matched male mice of the same genotype. These findings imply that androgen receptors (ARs) contribute to spatial learning and memory, posing the question as to whether transgenic expression of AR in female mice might modulate hippocampal-dependent learning and memory under baseline conditions and after local brain irradiation. Hippocampal-dependent novel location recognition was comparable in wild-type and AR-Tg female mice. This function was impaired after irradiation in AR-Tg but not wild-type mice. In contrast, sham-irradiated wild-type and AR-Tg female mice showed hippocampal-independent novel location recognition, and this was not affected by radiation. After the second day of hidden platform training, in a water maze probe trial, sham-irradiated and irradiated AR-Tg female mice showed spatial memory retention but irradiated wild-type mice did not. After the third day of hidden platform training, only irradiated wild-type female mice did not show spatial memory retention in the water maze probe trial. Both sham-irradiated and irradiated wild-type and AR-Tg female mice showed passive avoidance learning and memory. These data support an important role for AR in spatial memory retention in water maze probe trials in female mice under baseline conditions and after cranial irradiation.     

Mechanisms of long-term memory

Long-term potentiation (LTP) of the hippocampus provides an excellent model on which to build hypotheses for the laying down of memories in the cerebral cortex. After repetitive activation, the primary happening seems to be the increase in transmitter sensitivity brought about by the increased Ca2+ in the recipient neurons. There may be secondary presynaptic changes. The extreme duration of the LTP may require structural changes of the synaptic spines. The hippocampus plays an essential role in the laying down of cognitive memories, the pathway to the frontal lobe being via the MD thalamus. The thalamo-cortical fibres activate stellate cells whose axons make climbing fibre-like ramifications up the apical dendrites of the pyramidal cells. On the Marr hypothesis repetitive conjunction of synaptic activation by these climbing fibres with synaptic activation by horizontal fibres on the apical dendrites produces prolonged potentiation of the horizontal fibre synapses, which is the neural basis of memory. Presumably this is a consequence of the raised Ca2+ of the apical dendrites, acting as it does on the hippocampal LTP. It will be considered how this elemental unit for cerebral memory can be developed into the varieties of cerebral memories that have been located by study of the regional cerebral blood flow during their retrieval. These sites for memory are in the frontal lobe, usually in the superior prefrontal area.     

Glucagon-like peptide 2 improves intestinal wound healing through induction of epithelial cell migration in vitro-evidence for a TGF--beta-mediated effect

BACKGROUND/AIMS: In vitro studies suggest that glucagon-like peptide 2 (GLP-2), secreted from enteroendocrine cells in the gastrointestinal tract after food intake, is able to ameliorate mucosal injury in settings of human disease characterized by injury and dysfunction of the intestinal mucosal epithelium. We evaluated this potential of GLP-2 after epithelial trauma by using two in vitro models measuring intestinal epithelial cell proliferation and cell migration. MATERIALS AND METHODS: Injuries were induced in confluent monolayers of the small intestinal cells lines IEC-6 and IEC-18, as well as in the colonic cell lines Caco-2 and Colo 320. GLP-2 (50-500 nM) or other peptides were added to the media. Wound healing was investigated after 24 h by quantification of the number of cells migrating across the wound edge. Proliferation of cells was assessed by using photometric mitochondrial incorporation measurement of MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide). Monoclonal TGF-beta antibodies were added to wounded monolayers to examine whether the GLP-2-induced wound healing was TGF-beta-mediated. RESULTS: Migration assessments revealed a significant stimulation of GLP-2-induced migration in IEC-6 and IEC-18 monolayers compared to the placebo group. No effect was observed in the colon cancer cell lines Caco-2 and Colo 320. Results of the proliferation assays show a significant inhibition of proliferation by GLP-2 in small intestinal cell lines whereas a dose-dependent stimulation of proliferation in colonic epithelial cells was observed. Addition of neutralizing TGF-beta1 antibodies to wounded IEC-6 and IEC-18 monolayers incubated with GLP-2 significantly reduced the number of migrating cells to the level of the placebo group. CONCLUSIONS: In our in vitro model, it was shown that the GLP-2-induced improvement of intestinal wound healing is TGF-beta-mediated. These effects were predominant in the epithelium of the small intestine compared to colonic epithelium. Our findings provide further insight into mechanisms leading to GLP-2-induced mucosal wound healing. These results suggest that GLP-2 or analogues of this peptide may potentially be useful for the treatment of intestinal disorders characterized by injury and ineffective repair of the intestinal mucosa.     

Rapid memory CD8+ T-lymphocyte induction through priming with recombinant Mycobacterium smegmatis

The most promising vaccine strategies for the induction of cytotoxic-T-lymphocyte responses have been heterologous prime/boost regimens employing a plasmid DNA prime and a live recombinant-vector boost. The priming immunogen in these regimens must elicit antigen-specific memory CD8+ T lymphocytes that will expand following the boosting immunization. Because plasmid DNA immunogens are expensive and their immunogenicity has proven disappointing in human clinical trials, we have been exploring novel priming immunogens that might be used in heterologous immunization regimens. Here we show that priming with a prototype recombinant Mycobacterium smegmatis strain expressing human immunodeficiency virus type 1 (HIV-1) gp120-elicited CD4+ T lymphocytes with a functional profile of helper cells as well as a CD8+ T-lymphocyte population. These CD8+ T lymphocytes rapidly differentiated to memory cells, defined on the basis of their cytokine profile and expression of CD62L and CD27. Moreover, these recombinant-mycobacterium-induced T lymphocytes rapidly expanded following boosting with a recombinant adenovirus expressing HIV-1 Env to gp120-specific CD8+ T lymphocytes. This work demonstrates a remarkable skewing of recombinant-mycobacterium-induced T lymphocytes to durable antigen-specific memory CD8+ T cells and suggests that such immunogens might be used as priming vectors in prime/boost vaccination regimens for the induction of cellular immune responses.     

Phytochrome-mediated long-term memory of seeds

The question is how long phytochrome, stored within the cytoplasm of plant diaspores, may stimulate their germination. This question arose from the observation that soil cultivations in darkness for weed control gave inconsistent results. Namely, after a single nighttime or daytime cultivation during spring and summer, differences in weed emergence became hardly detectable after a period of six weeks. However, after nighttime and daytime cultivations in late autumn, emergence differences persisted for up to nine months. To examine whether this differing memory effect is phytochrome-mediated, seeds of Chenopodium album and Stellaria media were sown in pots with wet peat, either in daylight or after sunset. In the latter, seeds were irradiated with far-red light for one day prior to being covered and buried. For more than two years the far-red irradiated seeds produced significantly reduced emergence, indicating that germination and emergence of weeds in the field may be supported by maternal far-red absorbing seed phytochrome B(fr) over several months or even years. This conclusion allows refining of the strategy of lightless tillage.     

Effects of systemic pancreastatin on memory retention

Pancreastatin, a peptide isolated from the pancreas, was shown to enhance memory retention after peripheral administration in mice when administration following T-maze footshock avoidance training. The effect of pancreastatin on memory retention, one week after training, was time dependent showing enhancement of retention when pancreastatin was administered 0 and 30 min but not 60 min after training. Pancreastatin reversed the amnesia produced by scopolamine. The pancreastatin fragment (33-49) also enhanced memory. Pancreastatin did not increase glucose in vivo. We conclude that peripherally administered pancreastatin modulates memory processing.     

High-cholesterol diets impair short-term retention of memory in alloxan-induced diabetic mice, but not acquisition of memory nor retention of memory in prediabetic mice

Whether high-cholesterol diets (HCD) induce a high incidence of memory deficits in diabetes requires to be established; if so, whether they induce impairments of memory acquired in the pre-diabetic stage as well as in the diabetic stage also needs to be elucidated, and part of the related mechanisms involved in this dysfunction should be determined. The mice were grouped into: normal mice fed normal diets (NN), diabetic mice fed normal diets (DN), normal mice fed HCD (NH), and diabetic mice fed HCD (DH). Animals were subjected to Morris water maze testing: 1) Learning in the pre-diabetic stage and memory retrieval in the diabetic stage; 2) Learning and memory retrieval in the diabetic stage. Following water maze testing, biochemical parameters were estimated in the animals. The results showed that significant impairments of memory retrieval, acquired in the diabetic stage, were observed only in DH group, neither in DN nor NH group in a short term compared with NN group. Biochemical parameters including fasting blood glucose, lipid peroxidation productions and acetylcholinesterase activities in frontal cortex and hippocampus increased more rapidly in DH group than those in the rest. These results indicate that HCD impair the diabetic retention of memory, but neither the diabetic acquisition of memory nor the pre-diabetic retention of memory in diabetic mice in a short term. Controlled HCD may be a strategy to prevent the loss of memory in diabetic individuals after they have acquired new information.